JP2009514597A - Bioabsorbable hemostatic gauze - Google Patents

Abstract

  A bioabsorbable, water-soluble, hemostatic cellulose-based gauze matrix structure has been described that includes one or more species of chitosan, etherified cellulose, nonionic surfactant Water-soluble polysaccharide hydrocolloids and / or gums. Decrystallized chitosan deacetylated to approximately 85% to 95% present in an amount from about 2% to about 15% by weight has been found to be particularly advantageous. Among other things, favorable properties have been found for rapid bleeding arrest and bioabsorption properties.

Description

Background of the present disclosure FIELD OF THE INVENTION The present invention relates generally to hemostatic compositions and gauze matrix structures containing hemostatic compositions, and more particularly to bioabsorbable and water-soluble to stop bleeding. Of cellulose-based compositions.

2. DESCRIPTION OF THE PRIOR ART Bleeding is the leading cause of death in accident victims and injured military personnel during combat. Therefore, it is very important to give first aid to suppress local bleeding.

  Cellulose-based materials such as cotton or regenerated cellulose fibers, regenerated cellulose sponges, cellulose gauze made from other cellulose fibers, and the like have been utilized to absorb body fluids and blood during surgery. A significant drawback in using such products in contact with tender or sensitive areas of the body, such as the eyes, scratches, incisions, etc. is that their cellulose sponges and fibers are typically In other words, it has a rough, rough and / or tingling property. These properties of cellulose can cause irritation, cause skin or membrane laceration, and can cause infection in the wound. This cellulosic material can cause irritation when cut to various sizes by an emergency medical practitioner or first aid, perhaps in an emergency where speed is critical. Also, loose fiber fragments are typically formed along the cut surface. Thus, when the cut cellulose material is used in the eye, open wound and / or surgical site, these cut surfaces can cause irritation. In addition, loose fiber fragments can further irritate the skin or cell membrane and can be a source of infection.

  U.S. Pat. No. 4,543,410 discloses absorbent cellulosic structures that overcome some of the disadvantages of prior products, but these structures still have some significant drawbacks. Yes. For example, when loose fibers from these structures enter the wound, it may not be feasible to detect and remove all such fibers by visual inspection. Water-insoluble cellulosic materials are not absorbed by the body and can be a source of contamination or infection, exacerbating the wound healing process and delaying the patient's rapid recovery.

  When treating external bleeding, cotton gauze pads with the ability to absorb approximately 250 mL of blood are the primary dressing material currently used by the military and civilian trauma units. . These pads are typically bandage materials that are used passively, that is, such bandage materials typically do not initiate or accelerate blood clotting.

  A hemostatic bandage containing a fibrin glue formed by combining bovine fibrinogen and thrombin has been described by Larson, M. et al. J. et al. Arch. Surg. 130: 420-422 (1995), the purpose of this hemostatic compression bandage is to control the injured artery in a porcine model.

US Pat. No. 6,056,970 discloses a solid, fibrous bioabsorbable hemostatic composition containing a bioabsorbable polymer and a hemostatic compound such as thrombin or fibrinogen. As with collagen or other materials derived from animals or animal products, one drawback of using fibrin glue is the inherent nature of infecting diseases or other contaminants with its hemostatic composition. There are risks. That is, blood or other substances that function as a source of one or more components in the hemostatic composition can reduce the cost of the product by bypassing the purification procedure or requiring extraordinary perfect purification. It may contain other substances harmful to the patent intended to use the substance with pathogenic bacteria or its hemostatic composition that can be increased.

  Another significant drawback of some products in the prior art is that in order to effectively stop bleeding, their components must be kept separately during storage and transport and mixed together at the time of use. . For example, since the thrombin component degrades at high temperatures, it must typically be maintained at a temperature of 30 degrees C or lower, which cannot be cooled in a high temperature environment or during storage and transportation. It is not always convenient in an emergency kit intended for use in situations.

Chitosan is a form in which chitin, a naturally occurring polysaccharide, is partially or fully deacetylated. Like chitin, chitosan is the generic name for a group of polymers of acetylglucosamine with a degree of deacetylation between about 50 percent and 90 percent. Chitosan is a polysaccharide containing primary amine groups and has a distribution of β- (1-4) -linked D-glucosamine (deacetylated units) and N-acetyl-D-glucosamine (acetylated units). including. Chitosan is structurally similar to cellulose and differs in that the C-2 hydroxyl group of cellulose is replaced with a primary amine group in chitosan. Number of free amine groups (having about 6.3 pK _a) is formed into a chitosan polymer weak base. Both chitin and chitosan are insoluble in water, dilute aqueous base solutions and most organic solvents. However, unlike chitin, chitosan, like chitosonium salts, is soluble in dilute acid aqueous solutions, usually carboxylic acids. Thus, solubility in dilute aqueous acid is a simple way to distinguish between chitin and chitosan.

  Chitosan and its derivatives are useful for making surgical bandages and suture materials, ocular bandages and lenses. Chitosan can form water-soluble salts with many organic and inorganic acids. Such salts are typically biologically compatible with skin, hair and most living tissues. Such chitosonium derivatives may be useful for biomedical applications because some chitosan salts can promote rapid healing in injured tissues. The histocompatibility and accelerated healing properties of these chitosan salts are common to many covalent chitosan derivatives, covalent chitin derivatives, chitosan and chitin.

  However, chitosan derivatives are typically very crystalline polymers and are difficult to prepare. U.S. Pat. No. 4,929,722 discloses a decrystallization process in which chitosan can be made into an amorphous structure expanded with a diluent. This form of chitosan is typically more suitable for the formation of derivative compounds.

  US Pat. No. 5,800,372 proposes microfibrillar collagen and superabsorbent polymer combined in a hemostatic bandage that both absorb blood and induce clotting. However, its drawbacks include a relatively slow cessation of bleeding, poor controllability in terms of bioabsorbability, and the risk of disease transfer from the collagen donor to the patient.

US Pat. No. 5,047,244 describes a mucoadhesive carrier that releases a therapeutic agent in a controlled manner through mucosal tissue. The mucoadhesive carrier includes an anhydrous but hydratable polymer matrix and amorphous fumed silica. In some cases, a water insoluble film can be added, resulting in a non-tacky surface. In WO 91/06270, the same authors disclose a three-layer film for prolonging the delivery of the active ingredient in the oral cavity.

  U.S. Pat. No. 4,876,092 discloses a sheet-like adhesive preparation. The adhesive preparation includes an adhesive layer containing a water-soluble polymer and a water-insoluble polymer and a water-insoluble carrier. This preparation adheres to the oral mucosa, thereby releasing the active substance into the oral cavity. However, these devices are not completely bioabsorbable and thus leave the patient with certain discomfort resulting from a support layer that remains in the oral cavity after treatment is complete, leaving an insoluble residue primarily in the mouth. Will.

  Numerous attempts have been made to introduce a soft film support to reduce the unpleasant sensation in the oral cavity caused by the rigidity and inflexibility of this support layer. EP 0200508B1 and EP0381194B1 disclose the use of polyethylene film, polyvinyl acetate, ethylene-vinyl acetate copolymer, metal foil, fabric or laminate of paper and plastic film and similar materials as flexible film supports. Wherein, synthetic resin-like polyethylene, vinyl acetate homopolymer and ethylene-vinyl acetate are preferred materials. CA1263312 discloses the use of polyolefins such as polyethylene, polypropylene, polyester, PVC, etc., and nonwovens as soft support materials.

  However, these devices leave a significant amount of residue in the patient due to the insoluble nature of the support film in the water. This causes an unpleasant sensation. One approach to overcoming this problem has been to develop a fully degradable mucoadhesive film or a film that is completely soluble in saliva. Fuchs and Hilmann (DE 24498565) describe uniform water-soluble cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose or methylhydroxypropyl cellulose as film formers.

  Both documents DE 36306603 and EP 0 219 762 disclose the use of swellable polymers (such as gelatin or corn starch) as film formers, which slowly disintegrate when applied to the oral cavity. This releases the active ingredient incorporated in the film. These same polymers can also be used to prepare films intended for use in tooth cleaning, as described in EP 0 454 446 B1. These preparations are initially rigid and then soften later, thus still creating an unpleasant sensation in the mouth. Accordingly, there remains a need in the art for compositions for use in the oral cavity that reduce or avoid unpleasant sensations in the patient's mouth.

  US Pat. No. 6,177,096 provides water-soluble polymers with one or more plasticizers or surfactants, one or more polyalcohols, and instant wetting on the oral mucosa. Discloses methods and compositions for avoiding unpleasant sensations by incorporating pharmaceutically or cosmetically active ingredients that are intended. Being bioabsorbable is an improvement over many previous non-bioabsorbable bandages. However, one drawback is associated with limited liquid absorbency, slow hemostatic capability, and poor controllability in terms of its body absorbability.

The use of polysaccharides as wound dressings and wound healing compositions has also been studied. Alginate gels, films, fibers and / or fabrics have been proposed as wound dressings. The solubility of the alginate can vary depending on the ratio of sodium alginate (soluble) to calcium alginate (insoluble) in their composition.

  EP-A-0227553 describes a sodium / calcium alginate sponge for use as a hemostatic bandage. This sponge is formed by mixing an aqueous solution of sodium alginate with a solution of calcium chloride under an inert atmosphere. After this, the mixture is lyophilized. The resulting alginate sponges are used as wound dressings, either overly soluble (if sodium content is high) or too brittle (if calcium content is high) It is reported that it was not convenient to do.

  Other polysaccharides have been proposed for use as or in wound dressing materials, which are glucosaminoglycans such as hyaluronic acid and its derivatives and heparin, as well as other natural Polysaccharides such as chitin. It has also been proposed to form wound dressing gels using naturally occurring polysaccharide gums. Specifically, WO-A-9106323 and WO-A-9306802 suggest the use of xanthan or guar gum as a gelling agent in the preparation of wound dressing gels. U.S. Pat. No. 4,994,277 states the use of certain aqueous gels containing xanthan in surgery to reduce tissue adhesion. These gels may also contain galactomannans, such as guar gum to increase viscosity, or gelatin. U.S. Pat. No. 4,341,207 describes a multilayered pressure ulcer comprising a wound contact layer comprising a mixture of water-soluble or swellable hydrocolloids such as guar gum and other binders for those hydrocolloids. A ulcer bandage is described.

  The use of a mixture of these two types of polysaccharides can result in a material with controllable solubility that can be tailored to the respective wound dressing application. US Pat. No. 6,309,661 describes a lyophilized solid bioabsorbable bandage made using a mixture of xanthan gum and at least one galactomannan, such as guar gum or locust bean gum. Thus, it is stated that the weight ratio of xanthan to total galactomannan should be in the range of 10:90 to 90:10. More preferably, the ratio ranges from 25:75 to 75:25. Being bioabsorbable is an improvement over many previous non-bioabsorbable bandages and can typically control water solubility better than other conventional bandages. Disadvantages include relatively poor performance with respect to rapidly stopping bleeding, performance with respect to healing speed, performance with respect to liquid absorption capacity, and performance with respect to speed of liquid absorption.

  Accordingly, there is a need in the art for hemostatic compositions and products that have improved performance characteristics in one or more of the following: among others, the speed of bioabsorbability and / or Controllability, reduced risk of infection and / or irritation, reduced side effects, hypoallergenicity, speed of bleeding cessation and / or accelerated healing, high fluid absorbency, rapid fluid absorption, controllable consistency And durable.

SUMMARY OF THE INVENTION Some embodiments of the invention generally include a bioabsorbable, water-soluble, hemostatic cellulose-based gauze matrix structure, a hemostatic composition useful for cooperating with gauze structures. Articles, methods of making and using, and products useful for wound healing. Such gauze matrix structures according to some embodiments of the present invention, when judged in comparison with many other currently used therapeutic means and therapeutic products, include one or more of the following: Can be effective: rapidly stop bleeding from the wound and / or reduce or minimize the risk of infection and / or increase the speed of healing and / or deleterious side effects To reduce. A hemostatic cellulose-based gauze according to some embodiments of the present invention typically includes some or all of the following: one or more species of etherified cellulose, chitosan, One or more species of water-soluble polysaccharide hydrocolloids, and one or more species of nonionic surfactants. When one or more of these structures are applied to the body, typically an aqueous bodily fluid causes the fibers to swell and stick out the fibers and fibrils, thereby dissolving or sharp edges. Promotes smoothing. Thus, irritation is reduced or substantially eliminated.

  Gauze matrix structures according to some embodiments of the present invention generally exhibit superior hemostatic properties. Inclusion of uniformly dispersed polysaccharide hydrocolloids in some embodiments of the present invention typically increases hemostatic efficacy. The use of polysaccharide gums and nonionic surfactant species in some embodiments of the present invention typically increases the controlled solubility characteristics of the gauze.

  Some embodiments of the present invention advantageously have a short bioabsorption time, the ability to rapidly stop bleeding from a wound, the ability to reduce or minimize the risk of infection, the ability to increase the speed of healing, and side effects It relates to the preparation of gauze matrix structures based on appropriately bioabsorbable and water-soluble hemostatic cellulose with advantageous abilities such as the ability to reduce or eliminate.

  An object of some embodiments of the present invention is to provide an improved solid bioabsorbable hemostatic material that is typically used as a wound dressing. Desirable properties with improved materials according to some embodiments of the present invention include one or more of the following properties: rapid cessation of bleeding, rapid healing, controllable solubility in body fluids, internal body Short bioabsorption time, reduced side effects, low allergenicity, low risk of infection, high liquid absorbency, rapid liquid absorbency, durable controllable consistency, biodegradability, and low cost.

  The purpose of some embodiments of the present invention is to provide an improved solid bioabsorbable hemostatic material that is immediately absorbed by the body and thus does not require removal of the material from the body after surgery or other treatment. Is to provide. This property, among other things, can simplify the surgical procedure and reduce pain experienced during the post-operative recovery period.

  The purpose of some embodiments of the present invention is to produce a solid bioabsorbable hemostatic material by combining some or all of the benefits resulting from the use of the following ingredients: (1) Rapid Water-absorbable, bioabsorbable cellulose polymer with bioabsorption, high liquid absorbency and biodegradability, resulting in rapid cessation of bleeding and rapid healing; (2) reduced stiffness, wet / dry strength ratio Fully deacetylated and decrystallized chitosan resulting in improved lint and reduced luffing and sloughing; (3) enhanced rapid wettability and oral hemostatic bandage Can leave a pleasant sensation in the mouth when used as (and sometimes acts synergistically with chitosan to One or more surfactants; (4) provide controllable solubility in body fluids and are etherified in their bioabsorbability A polysaccharide gum that can function synergistically with cellulose.

  Accordingly, some embodiments of the present invention provide solid, bioabsorbable materials for use as effective wound dressings by activating one or more clotting factors.

  A further object of some embodiments of the present invention is to provide a method for producing etherified cellulose having desirable properties.

  It is a further object of some embodiments of the present invention to provide a method of producing a solid, bioabsorbable material with one or more desirable characteristics listed above.

DETAILED DESCRIPTION Some embodiments of the invention relate to one or more of the following:
A composition of a bioabsorbable, water-soluble hemostatic gauze matrix having a short bioabsorption time, wherein the one or more etherified celluloses are present in an amount from about 55% to about 95% by weight; Chitosan in the range of about 0.5 wt% to about 15 wt%, one or more water-soluble polysaccharide gums in the range of about 5 wt% to about 50 wt%, about 0.1 wt% to about Bioabsorbable, containing one or more nonionic surfactants in the range of up to 5% by weight and acetic acid (preferably reagent grade) in the range of about 0.01% to about 10% Water-soluble hemostatic gauze matrix composition. The etherified cellulose described above is typically selected from the group consisting of hydroxypropylcellulose, methylhydroxypropylcellulose, methylhydroxyethylcellulose. More advantageous percentage compositions by weight of these compositions include from about 65% to about 85% one or more etherified celluloses, from about 1% to about 5% chitosan, from about 15% to about 25%. % Of one or more water-soluble polysaccharide hydrocolloids and from about 0.2% to about 2.0% of one or more surfactants.

  The etherified cellulose advantageously used in some embodiments of the composition is selected from the group consisting of hydroxypropylcellulose, methylhydroxypropylcellulose and methylhydroxyethylcellulose. The composition can comprise individual etherified polymers, any two combinations or all three combinations in various ratios. Our studies show that the most advantageous combination is hydroxypropylcellulose, methylhydroxypropylcellulose and methylhydroxyethylcellulose in a ratio of approximately 1: 2: 1.5.

  Etherified cellulose according to some embodiments of the present invention advantageously comprises hydroxypropylcellulose having a DS (degree of substitution) in the range of about 0.3 to about 2.5, about 0.6 to about 2. Selected from the group consisting of methyl hydroxypropyl cellulose having a DS in the range of 8 and methyl hydroxyethyl cellulose having a DS in the range of about 0.5 to about 2.6. Particularly preferred etherified celluloses are hydroxypropylcellulose having a DS in the range of about 0.8 to about 2.0, methylhydroxypropylcellulose having a DS in the range of about 1.2 to about 2.5, and Selected from the group consisting of methyl hydroxyethyl cellulose having a DS in the range of about 1.0 to about 2.2.

Etherified cellulose prepared according to some embodiments of the present invention typically has one or more advantageous properties, including one or more of the following: bleeding Rapid cessation, rapid healing, short bioabsorption time, high liquid absorbency and biodegradability. Among other things, short bioabsorption time is a particularly advantageous feature of some embodiments of the present invention. The hemostatic bandage with the shortest bioabsorption time currently on the market has a bioabsorption time of about 48 hours. However, gauze matrix structures according to some embodiments of the present invention can be completely dissolved in the body in as little as two hours. This short bioabsorption time means that the body has reduced resistance to dressing material, which is essentially foreign material left in the body after surgery. Thus, such embodiments provide a high level of safety and a reduced risk of infection.

  Chitosan is a high molecular weight linear carbohydrate that typically includes acetylated units and deacetylated units. Chitosan is a deacetylated derivative of chitin. Chitin is a glucosamine polysaccharide that is structurally similar to cellulose. Chitin is typically produced in commercial quantities from crustacean shells. Chitin is insoluble in most common solvents. However, chitosan is soluble in acidified water due to the presence of basic amino groups. Depending on the source and extent of deacetylation, chitosan can vary in molecular weight and free amine content. In a sufficiently acidic environment, their amino groups become protonated and chitosan behaves as a cationic polyelectrolyte. Chitosan has been used as an effective dry strength additive for paper, among other applications.

  The chitosan used in some compositions according to some embodiments of the present invention is selected from the group consisting of decrystallized chitosan that is approximately 85% to 90% deacetylated. Particularly advantageously, the ratio of etherified cellulose to deacetylated decrystallized chitosan ranges from about 10: 1 to about 15: 1.

  When 85% to 90% deacetylated decrystallized chitosan is used, the pH of the fibrous pulp in the preparation stage is about 4.5-6 to achieve substantially complete water solubility. Should be adjusted to be in the range of 0.0, typically using reagent grade acetic acid (typically 84% weight-weight (w / w) concentration). When used in combination with the suggested nonionic surfactant in the composition where water-soluble deacetylated decrystallized chitosan is suggested, the gauze matrix has improved wet / dry strength ratio, As well as significantly softening, with reduced linting and sluffing. These properties are very advantageous in reducing or substantially eliminating the possibility of contamination in the wound area. Also, the 85% to 90% percentage of deacetylated chitisen used in the formulation also affects bioabsorption time. Generally speaking, the higher the percentage of chitosan used, the longer the bioabsorption time. Therefore, it is necessary to balance the various components in order to achieve hemostatic gauze with optimal or near optimal performance.

  Xanthan is a synthetic water-soluble biopolymer typically made by fermentation of carbohydrates. Solid materials formed from xanthan alone or galactomannan alone are typically very soluble in water, which is an advantageous property for bioabsorbable dressings. However, typically such materials do not provide the necessary structure for a wound dressing to survive for an appropriate period of time. Therefore, it is rugged enough to withstand manual pressure, and in use, especially in an emergency situation, such as fatal trauma where it is extremely important to stop blood flow as quickly as possible There is a need in the context for a bioabsorbable hemostatic composition that can be used reasonably easily.

  The use of a mixture of etherified cellulose and polysaccharide gums (preferably two) according to some embodiments of the present invention can be tailored to optimum or near-optimal properties for each wound dressing application. Resulting in materials with highly controllable solubility. Solid bandages made with a mixture of etherified cellulose, chitosan, nonionic surfactant, xanthan gum and at least one galactomannan, such as guar gum or locust bean gum, are: Healing, controllable solubility in body fluids, short bioabsorption time, substantial absence of side effects, low allergenicity, low risk of infection, high liquid absorption, fast liquid absorption, durable but controllable It has been found to have a number of advantageous properties, including consistency, biodegradability, and low cost.

  Galactomannans are polysaccharides that contain both galactose and mannose residues. Advantageously, these galactomannans are guar gum (where the ratio of galactose to mannose is about 1: 2), locust bean gum (where the ratio of galactose to mannose is about 1: 4). ) And mixtures thereof.

  The water-soluble polysaccharide hydrocolloid used in the composition according to some embodiments of the present invention is advantageously selected from the group consisting of glucosaminoglycans and some naturally occurring gums. Particularly advantageous glucosaminoglycans for use in some embodiments of the present invention include guar gum and locust bean gum. The above-mentioned naturally occurring gums include xanthan gum and gum arabic. Particularly advantageous use levels of polysaccharide gums in some embodiments of the present invention range from about 15% to about 30%. A particularly advantageous ratio of etherified cellulose to glucosaminoglycan and naturally occurring gum ranges from about 10: 3: 2 to about 10: 2: 1.

  Important advantages of using a combination of etherified polymer and polysaccharide gum according to some embodiments of the present invention include: (1) the type of etherified polymer and polysaccharide gum used and Synergistic effect on solubility in body fluids that can be obtained by changing the ratio. For example, gauze made of etherified hydroxypropylcellulose, methylhydroxypropylcellulose and methylhydroxyethylcellulose in a ratio of about 2: 1.5: 1.25 is essentially completely absorbed by the body in about 4 hours. Can be done. However, if hydroxypropylcellulose, methylhydroxypropylcellulose, methylhydroxyethylcellulose, guar gum and xanthan gum are used in a ratio of about 2: 1.5: 1.25: 1.00: 1.15, body absorption The time is reduced to about 2 hours. (2) By changing the type and ratio of the etherified polymer and polysaccharide gum used, it is possible to increase versatility for a variety of different applications and is advantageous for a variety of different therapeutic applications. It is possible to make a special order of hemostatic gauze with a specific absorption time. Advantageously, the dispersion is in the form of a solution or gel and the solvent is an aqueous solvent. More preferably, the solvent consists essentially of water. Advantageously, the total weight concentration of xanthan and galactomannan in the dispersion according to some embodiments of the invention ranges from about 2 mg / ml (milligram / milliliter) to about 20 mg / ml. The dispersion will typically be a clear aqueous gel.

  The nonionic surfactant component used in some compositions according to some embodiments of the invention is advantageously saturated and / or unsaturated primary, secondary, and / or Or selected from the group consisting of branched amines, amides, amine-oxides, fatty alcohols, fatty acids, alkylphenols, and / or alkylaryl carboxylic acid and / or ester compounds, each typically alkyl or alkylene Having from about 6 to about 22 carboxyl groups in the chain, wherein at least one active hydrogen of said compound is intended to provide from about 8 to about 20 HLB (Hydrophilic Lipophilic Balance) , Ethoxylated with about 30 ethylene oxide moieties.

The surfactant used according to some embodiments of the present invention may be one or more non-ionic surfactants. When a combination of surfactants is used, the first component may be an aliphatic alcohol, while the second component may be any other primary, secondary, and / or There may be branched amines, amides, amine-oxides, fatty acids, alkylphenols, and / or alkylaryl carboxylic acid and / or ester compounds, advantageously each having from about 10 to about 18 in the alkyl or alkylene chain. Having at least one carboxyl group, wherein at least one active hydrogen of the aforementioned compound is ethoxylated with about 30 ethylene oxide moieties to provide an HLB in the range of about 12 to about 18. Yes.

  In order to achieve the desired properties for immediate wettability or very rapid wettability, the use level of chitosan should be in the range of about 2% to about 15% and the first of the binary surfactant mixture The ratio between the first and second components should be kept within the range of about 1: 8 to 1: 2, preferably between about 1: 5 and about 1: 3. The total surfactant concentration desired in the final product depends on the properties of the other ingredients, but is usually advantageously in the range of about 0.1% to about 3% (w / w) Advantageously, it is generally in the range from 0.1% to 1.5% (w / w).

  Fatty alcohols are typically used to achieve the desired level of softness of the product. Examples of fatty alcohols include glycerol, polyethylene glycol, propylene glycol, glycerol monoesters with fatty acids or other aliphatic alcohols typically used in the pharmaceutical field. The concentration of fatty alcohol in the product is usually in the range of between about 0.1% to about 1.5% (w / w).

  The raw materials used in the production of etherified cellulose according to some embodiments of the present invention include a source of cellulose, typically cotton, absorbent cotton, regenerated cellulose, sponge, fibrillated wood pulp, among other things. Including.

  A method for producing etherified cellulose according to some embodiments of the present invention includes the steps of placing the above-described ingredients in a closed chemical reactor and adding an alkali metal hydroxide. Those substances used are preferably aqueous sodium hydroxide, aqueous potassium hydroxide. It is also possible to use halogenated alkyl compounds such as, among others, methyl chloride, ethyl chloride and propyl chloride, and among others chloroacetic acid, chloropropanoic acid and chlorobutanoic acid. Additional alkenyl oxides can also be used, such as ethylene oxide and propylene oxide, among others. The mixture is heated at a temperature from about 30 degrees C to about 160 degrees C for about 1 to 6 hours. Further advantageous heating parameters have been found to be about 80 ° C. to about 150 ° C. for about 1-2 hours, or about 60 ° C. to about 150 ° C. for about 1-3 hours.

  After this, the product is about 4.5-8 using C1-C5 lower alkyl alcohols including methanol, ethanol, propanol, butanol, pentanol and isopropyl alcohol with an acid such as acetic acid or phosphoric acid. Neutralized to pH. The resulting product is then washed with approximately 70% to 90% ethanol until the halogen content in the product is below about 1%. Finally, the product is lyophilized and micronized. Etherified cellulose according to some embodiments of the present invention is hydroxypropylcellulose (having a DS in the range of about 0.3 to about 2.5), methylhydroxy having a DS of about 0.6 to 2.8. Selected from the group consisting of propylcellulose and methylhydroxyethylcellulose having a DS of about 0.5 to 2.6.

  A method of producing a bioabsorbable, water-soluble hemostatic gauze matrix according to some embodiments of the present invention comprises one or more etherified cellulose compounds (typically as described herein) in a non-aqueous solvent. A compound produced as described elsewhere) and a hemostatic compound to form a fibrous pulp, said hemostatic compound typically comprising chitosan, one Or comprising one or more water-soluble polysaccharide gums and one or more surfactants.

  The non-aqueous solvents described above are advantageously from linear or branched C1-C5 alcohols, ketones, aliphatic ethers, alicyclic ethers, esters, nitrites and aliphatic halogenated hydrocarbons. Selected from the group consisting of Advantageously, the solvent used is an alcohol of 95% to 100% ethanol. In some embodiments of the invention, high shear mixing is used to provide a substantially uniform dispersion of the material. The fibrous pulp is collected on a forming fabric. The term “forming fabric” refers to a material that is typically used during the papermaking process that allows drainage of the pulp solution while retaining the fibers. The forming fabric described above provides mechanical support, imparts surface properties during the pressing and drying process, and is then peeled from the dried paper product. The forming fabric may be of various materials including, but not limited to, a Teflon or stainless steel mesh screen, and is advantageously a polyester fabric. In other embodiments, the fibrous pulp is collected on a forming fabric under vacuum conditions. The collected wet pulp is subjected to a heat compression process and a freeze-drying process. The product is first frozen for about 15-40 minutes at a temperature ranging from about −30 ° C. to about −50 ° C. and then lyophilized. A typical cycle for making a sponge is from about -30 degrees C to about +25 degrees C overnight.

  The fibrous pulp is then subjected to a papermaking process to form a paper product. This papermaking process first separates the fibrous pulp from the non-aqueous solvent and, on top of that, the fibers on a forming fabric comprising a stainless steel mesh, a polyester fabric, a Teflon mesh, among others. Collecting the fibrous pulp, and then treating the collected fibrous pulp by heat compression. Thereafter, the pulp is subjected to a vacuum process for the purpose of defoaming. The resulting product is then pressed and lyophilized into a sponge form.

  In some embodiments of the present invention, the method comprises precipitating the components of the hemostatic composition separately or together in a non-aqueous solvent, under conditions sufficient to form a fibrous pulp. Combining the precipitated components, followed by collecting, pressing and drying the fibrous pulp to produce a solid, bioabsorbable hemostatic composition. Those materials according to some embodiments of the invention may be in the form of a sponge. The sponge material according to some embodiments of the present invention may be provided in any shape, but is advantageously provided as a wound dressing layer having a thickness from about 1 mm to about 5 mm. Advantageously, the sponge material has a water absorption of at least about 30 g / g.

  Some embodiments of the invention use the hemostatic composition for topical treatment to stop bleeding from a wound due to trauma, surgery or other causes. In addition, the method according to some embodiments of the present invention includes one or more hemostatic compositions for inhibiting or stopping bleeding in an organ, such as, among other things, liver, kidney, spleen, pancreas or lung. Including things. In addition, the methods of some embodiments may be performed during surgery, including but not limited to, abdominal, vascular, urological, gynecological, thyroid, neurosurgery, tissue transplantation, and dental surgery. Inhibiting or stopping bleeding or fluid loss. Some embodiments of the present invention provide the wound site with a solid hemostatic composition containing a bioabsorbable polymer and other ingredients that can provide beneficial wound healing benefits from the wound site. Related to how to stop blood loss quickly.

The hemostatic composition according to some embodiments of the present invention is advantageously maintained in contact with the wound site by applying light pressure for a time sufficient to stop the blood and cause blood clotting to occur. Is done. Generally, the hemostatic composition is applied for about 20 seconds to about 10 minutes, preferably about 20 seconds to about 5 minutes, more preferably about 20 seconds to about 2 minutes. In the meantime, it is maintained in contact with the surface of the wound. Some embodiments of the invention can also include an elastic bandage that can be wrapped around the patch to provide pressure to the wound site.

  The hemostatic composition according to some embodiments of the present invention can also be in the form of an adherent to an adhesive tape or can be attached to an adhesive backing in the form of a band aid. The type of adhesive used may be any type of medically acceptable adhesive. The adhesive used is advantageously of the porous type, which allows air to diffuse to the surface in contact with the wound. To meet various needs such as waterproofing, individual aseptic packaging, boxing including bandages of various shapes and sizes, or disposable pre-sterilized instruments such as scissors, scalpels, forceps, among others Various forms, shapes, sizes and types of hemostatic bandages can be made in kits designed for emergency or military use, which can also include tourniquets, elastic or inelastic bandages, and the like.

  Another advantage in some embodiments of the invention relates to ease of use. Typically, no specialized training is required. For example, in trauma packs for military personnel, rescue personnel, ambulance / emergency medical teams and firefighters, and by emergency room personnel, and in first aid kits for use by the general public, etc. Use on site is also feasible. Thus, the use of the hemostatic composition according to some embodiments of the present invention is expected to result in a reduction in the number of deaths due to trauma and is more serious in disaster situations by more effectively stopping bleeding. Can reduce the consumption of stored blood supplies that can cause a shortage.

  Pharmaceutically active ingredients and therapeutic agents that exhibit absorption problems due to limited solubility, degradation in the gastrointestinal tract or extensive metabolism are suitable for use in hemostatic compositions according to some embodiments of the present invention. Yes. Examples of such therapeutic agents include, among other things, hypnotics, analgesics, antiepileptics, stimulants, psychoactive drugs, neuromuscular blockers, antispasmodics, antihistamines, antiallergic drugs, cardiotonic drugs, antiarrhythmic drugs Includes drugs, diuretics, antihypertensives, vasopressors, antitussive expectorants, thyroid hormones, sex hormones, antidiabetics, antitumor agents, antibiotics, chemotherapeutics and anesthetics.

  The amount of drug incorporated into the hemostatic composition depends on the type of drug and the intended effect of the drug on the patient. Typical concentrations of drugs in hemostatic agents are between about 0.01% and 15% (w / w), but higher concentrations are necessary to achieve the desired effect. Also good.

  Flavoring agents (including, among other things, menthol, peppermint oil, spearmint oil and other exhaling compounds), and / or other substances used in cleaning teeth and / or mouth (eg, quaternary Ammonium base, etc.) may be incorporated into hemostatic compositions according to some embodiments of the present invention. Flavor enhancers such as tartaric acid, citric acid, vanillin and the like can also be used. FD & C (Food, Drug and Cosmetic Act) colorants, which may be optionally mixed with the hemostatic composition, must be safe in terms of toxicity and such use should be approved by the Food and Drug Administration .

  Next, specific procedures for producing hemostatic compounds, formulations and structures according to some embodiments of the present invention are presented. Such procedures are illustrative and not limiting and may involve different procedures derived from the techniques presented herein and / or different procedures related to the techniques presented herein. It will be apparent to those skilled in the art and such procedures are included within the scope of the present invention.

Example 1
Place 50 g of cotton wool in a closed chemical reactor. Add 750 ml of 50% w / w aqueous sodium hydroxide. The reaction is allowed to proceed for 2 hours at room temperature under constant stirring. Then about 150 ml of 50% w / w chloroacetic acid, 200 ml of ethylene oxide and 400 ml of propylene oxide are added to the solution and the reaction is continued for 8 hours. After this, the mixture is heated to 50 ° C. to 55 ° C. and the slurry is maintained at the elevated temperature for 5 hours with gentle stirring. Those derivatized fibers are recovered by filtration. The resulting product is neutralized with reagent grade acetic acid (84%) to a pH of about 7.0. After this, the recovered fibers are slurried in about 250 ml of 100% isopropanol. The fibers recovered from the last washing step are slurried in a medium containing a lower proportion of organic solvent to form a slurry with a consistency of about 10%. After pressurizing to drain excess liquid, the mats or sheets were lyophilized. The final product is hydroxylpropyl cellulose having a DS of 1.2 to 1.4. After this, the finished product is sterilized and packaged. Sterilization is advantageously accomplished by irradiating gamma radiation from a source of cobalt-60, or by other sterilization methods known in the art.

  75% by weight of the above lyophilized hydroxylpropylcellulose, 5% by weight of 90% deacetylated decrystallized chitosan (supplied by Indian Sea Foods), 12% by weight of gum arabic (supplied by Gum Technology Corp.), 7% locust bean gum (supplied by Danisco Inc.), 0.4% by weight glycerol and 0.1% by weight polysorbate 80 (polyoxyethylene sorbitan monooleate, (x) -sorbitan mono-9-octade 50 grams of a mixture containing cenoate poly (oxy-1,2-ethanediyl) is added to 1,000 ml of 95% ethanol and mixed in a Virearear 1700 homogenizer at 5,000 rpm for 50 seconds at high shear, after which ,result The pulp solution thus obtained is then diluted with 250 ml of 95% ethanol and this sample is collected on a forming fabric using a Millipore filter housing (diameter = 7.4 cm). Pressurize at 2 metric tons for 20 seconds, freeze to -40 C, lyophilize to form sponge, then package and sterilize. However, this is not an essential limitation and any procedure that results in a sterile product packaged to maintain sterility can be used.

Example 2
Place 50 g of cotton in a closed chemical reactor. Add 700 ml of 50% w / w aqueous potassium hydroxide solution. The reaction is allowed to proceed for 2 hours at room temperature under constant stirring. Then about 100 ml of 50% w / w chloroacetic acid, 50 ml chloropropanoic acid, 400 ml ethylene oxide and 200 ml propylene oxide are added to the solution and the reaction is continued for 8 hours. The resulting product is neutralized with reagent grade acetic acid (84%) to a pH of about 6.0. After this, the finished product is washed with 70-90% ethanol until the chlorine content in the product is below 1%. This final product is methylhydroxylpropylcellulose having a DS of 1.0 to 1.2. After this, the finished product is lyophilized, packaged and sterilized.

75% by weight of the above lyophilized methylhydroxylpropylcellulose, 5% by weight of 90% deacetylated decrystallized chitosan, 12% by weight gum arabic, 7% guar gum, 0.4% by weight propylene glycol and 50 grams of a mixture containing 0.1 wt% polysorbate 80 (polyoxyethylene sorbitan monooleate, (x) -sorbitan mono-9-octadecenoate poly (supplied by oxy-1,2-ethanediyl)) Is added to 1,000 ml of 95% ethanol and mixed in a Virearear 1700 homogenizer with high shear for 30 seconds at 4,500 rpm, after which the resulting pulp solution is diluted with 250 ml of 95% ethanol. Sample, Millipore filter housing (Wet diameter = 7.4 cm) is collected on the forming fabric, and the wet sample is pressed at 2 metric tons for 30 seconds, frozen to −40 ° C. and lyophilized to form a sponge. Then package and sterilize.

Example 3
10 g of regenerated cellulose is placed in a closed chemical reactor. Add 150 ml of 50% w / w aqueous sodium hydroxide solution. The reaction is allowed to proceed under constant stirring for about 1 hour at room temperature. Then about 30 ml of 50% w / w chloroacetic acid, 65 ml of ethylene oxide and 160 ml of propylene oxide are added to the solution and the reaction is continued for 8 hours. The resulting product is neutralized with reagent grade acetic acid (84%) to a pH of about 6.2. After this, the finished product is washed with 70-90% isopropyl alcohol until the chlorine content in the product is below 1%. The final product is hydroxylpropyl cellulose having a DS of 1.2 to 1.4. After this, the finished product is lyophilized, packaged and sterilized.

  75% by weight of the above lyophilized hydroxylpropylcellulose, 5% by weight of 90% deacetylated decrystallized chitosan, 8% by weight of xanthan gum, 11% of locust bean gum, 0.4% by weight of propylene glycol and 50 grams of a mixture containing 0.1% by weight of 1.5 g of Kollidon 30 (polyvinylpyrrolidone, povidone, supplier: BASF) is added to 1,000 ml of 95% ethanol and in a Vishear 1700 homogenizer at 5,000 rpm. Mix at high shear for 50 seconds. After this, the resulting pulp solution is diluted with 250 ml of 95% ethanol. The sample is collected on a forming fabric using a Millipore filter housing (diameter = 7.4 cm). The wet sample is pressurized at 2 metric tons for 20 seconds, frozen to -40 degrees C, lyophilized to form a sponge, and then packaged and sterilized.

  While various embodiments incorporating the teachings of the present invention have been shown and described in detail herein, those skilled in the art will recognize many other modified implementations that still incorporate these teachings. Forms can be easily devised.

Claims (22)

A hemostatic composition comprising:
One or more species of chitosan; and one or more species of etherified cellulose; and one or more species of nonionic surfactants; and polysaccharide hydrocolloids, polysaccharide gums And one or more water soluble species selected from the group consisting of and mixtures thereof;
A hemostatic composition comprising:   The composition of claim 1, wherein the one or more species of etherified cellulose is selected from the group consisting of: hydroxypropylcellulose, methylhydroxycellulose, methylhydroxyethylcellulose, and mixtures thereof.   The composition of claim 2, wherein the one or more species of etherified cellulose is a mixture of hydroxypropylcellulose, methylhydroxycellulose and methylhydroxyethylcellulose in a ratio of approximately 1: 2: 1.5. . The hydroxypropylcellulose has a DS in the range of about 0.3 to about 2.5; and the methylhydroxypropylcellulose has a DS in the range of about 0.6 to about 2.8. And the methyl hydroxyethyl cellulose has a DS in the range of about 0.5 to about 2.6;
The composition according to claim 2. The hydroxypropylcellulose has a DS in the range of about 0.8 to about 2.0; and the methylhydroxypropylcellulose has a DS in the range of about 1.2 to about 2.5. And the methyl hydroxyethyl cellulose has a DS in the range of about 1.0 to about 2.2;
The composition according to claim 2.   The composition of claim 1, wherein the one or more species of chitosan is selected from the group consisting of approximately 85% to approximately 90% deacetylated decrystallized chitosan and mixtures thereof.   The composition of claim 1, wherein the one or more species of chitosan is present in an amount ranging from about 2 wt% to about 15 wt%.   7. The one or more species of etherified cellulose and the one or more species of chitosan are present in a ratio ranging from about 10: 1 to about 15: 1. Composition.   The composition of claim 1, wherein the one or more water soluble species comprises xanthan gum and at least one galactomannan.   10. The composition of claim 9, wherein the at least one galactomannan is selected from the group consisting of gar gum, locust bean gum, and mixtures thereof.   11. The composition of claim 10, wherein the gar gum has a galactose to mannose ratio of about 1: 2, and the locust bean gum has a galactose to mannose ratio of about 1: 4.   The one or more water-soluble species is one or more species of glucosaminoglycan, and one or more species of natural selected from the group consisting of xanthan gum, gum arabic and mixtures thereof The composition of claim 1 comprising a gum resulting from   13. The composition of claim 12, wherein the one or more species of glucosaminoglycan is selected from the group consisting of gar gum, locust bean gum, and mixtures thereof.   The composition of claim 1, wherein the one or more water-soluble species is present in an amount ranging from about 15% to about 30% by weight.   The one or more species of etherified cellulose, the one or more species of glucosaminoglycan and the one or more species of naturally occurring gum are about 10: 3 by weight. The composition of claim 12 present in a ratio ranging from: 2 to about 10: 2: 1.   The one or more types of nonionic surfactants are: saturated or unsaturated primary, secondary or branched amines, amides, amine-oxides, aliphatic alcohols, alkylphenols, alkyls Arylcarboxylic acids, their esters and mixtures; wherein each nonionic surfactant of said one or more species is about 6 to about 22 in the alkyl or alkylene chain. The composition of claim 1 having up to 5 carboxylic acid groups and being sufficiently ethoxylated to provide an HLB in the range of about 8 to about 20.   The composition of claim 1, wherein the one or more species of nonionic surfactant is present in an amount ranging from about 0.1 wt% to about 3 wt%.   The composition of claim 1, wherein the one or more species of nonionic surfactant is present in an amount ranging from about 0.1 wt% to about 1.5 wt%. The one or more species of etherified cellulose is present in an amount from about 55% to about 95% by weight; and the one or more species of chitosan is from about 0.5% by weight. Present in an amount up to about 15% by weight; and the one or more water-soluble species is present in an amount from about 5% to about 50% by weight; and the non-one of the one or more species An ionic surfactant is present in an amount from about 0.1% to about 5% by weight; and further comprises acetic acid present in an amount from about 0.01% to about 10% by weight;
The composition of claim 1. The one or more species of etherified cellulose is present in an amount from about 65% to about 85% by weight; and the one or more species of chitosan is from about 1% to about 5%. Present in an amount up to% by weight; and said one or more species of water soluble polysaccharide gum is present in an amount from about 15% to about 25% by weight; and said one or more species Of nonionic surfactant is present in an amount from about 0.2% to about 2% by weight;
20. A composition according to claim 19. A method for producing etherified cellulose comprising:
a) Put the reactants in a closed chemical vessel and heat for a period of time from about 1 hour to about 6 hours in the range of about 30 degrees C to about 160 degrees C, thereby producing a first product And b) treating the first product with an acid to produce a second product having a pH in the range of about 4.5 to about 8; and c) the second product; Washing with approximately 70% to 90% ethanol until the halogen content is less than about 1%, thereby producing a third product; and d) lyophilizing said third product to a fine powder Step of converting;
Wherein the reactant is a source of cellulose, one or more species of alkali metal hydroxide, one or more species of halogenated alkyl compounds and optionally one or more of A process for producing etherified cellulose comprising a species of alkenyl oxide. A method for producing a hemostatic gauze comprising:
Mixing one or more species of etherified cellulose with a hemostatic compound in a non-aqueous solvent, thereby forming a fibrous pulp; and said fibrous pulp from said non-aqueous solvent Separating and collecting the fibrous pulp on a forming fabric; and pressurizing and freeze-drying the collected fibrous pulp;
Wherein the hemostatic compound comprises one or more species of chitosan, one or more species of water-soluble polysaccharide gums and one or more species of surfactants, Method for producing hemostatic gauze.